Blood coagulation is the key process involved in both haemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).
Coagulation is the result of a complex series of enzymatic reactions. One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin.
Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore, thrombin activates factor V and factor VIII leading to a “positive feedback” generation of thrombin from prothrombin.
Effective inhibitors of thrombin are thus known, and/or are expected, to be useful as anticoagulants and therefore useful in the therapeutic treatment of thrombosis and related disorders.
The early development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 411. Low molecular weight thrombin inhibitors have been described more recently in U.S. Pat. No. 4,346,078; International Patent Applications WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO 98/01422, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; and European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623 596.
In particular, international patent application WO 94/29336 discloses a group of compounds, including HOOC—CH2—(R)Cgl—Aze—Pab—H (in which Cgl represents cyclohexylglycine, Aze represents S-azetidine-2-carboxylic acid and Pab—H represents 4-aminomethyl-amidinobenzene), which is also known as melagatran (see Example 1 of WO 94/29336). International Patent Application WO 97/23499 discloses prodrugs of inter alia melagatran.
None of the above-mentioned documents disclose or suggest the administration of an active thrombin inhibitor in conjunction with a prodrug of that thrombin inhibitor, or indeed in conjunction with a prodrug of any thrombin inhibitor.
Deep venous thrombosis (DVT) and pulmonary embolism (PE) are major health problems, which may give rise to serious outcomes. In particular, PE may be fatal, or may result in the development of pulmonary hypertension and heart failure from recurrent embolism. DVT may result in post-thrombotic venous insufficiency and ulcers in the affected part of the body (e.g. leg). Both are common conditions, which have a great impact on worldwide healthcare costs.
There is a considerable incidence of DVT and PE following orthopaedic surgery. For example, in patients undergoing total hip replacement, the incidence of DVT in the absence of thromboprophylaxis may be as high as 45 to 57%. Further, the incidence of proximal DVT may be between 23 and 36%, and that of fatal PE, 0.34 to 6%. In patients undergoing total knee replacement in the absence of thromboprophylaxis, the postoperative incidence of DVT is between 40 and 84%, of proximal DVT is between 9 and 20%, and of fatal PE is between 0.2 and 0.7%. In patients undergoing general surgery in the absence of thromboprophylaxis, the postoperative incidence of DVT is about 25%. (Reference: Chest (1998) 114, 531S to 560S.)
Low-dose, subcutaneous (s.c.) unfractionated heparin is the most widely used current prophylactic treatment for venous thromboembolism resulting from orthopaedic and general surgery. The incidence of DVT after total hip replacement has been shown to be reduced (see Chest reference above).
The use of low-molecular weight heparin (LMWH) in the prophylaxis of DVT following total hip and knee replacement operations has been shown to further the reduce incidence (when compared to low dose unfractionated heparin), without a concomitant increase in bleeding (see Chest reference above).
However, prolonged treatment with heparins has been shown to give rise to an increased risk of osteoporosis. Heparins may also give rise to “heparin-induced thrombocytopenia” (HIT), are dependent on the plasma level of the endogenous thrombin inhibitor, antithrombin, and do not inactivate clot-bound thrombin.
Oral anticoagulants, such as warfarin (a vitamin K antagonist), has also been shown to be effective in reducing DVT after major surgery (see Chest reference above). However, due to the risk of bleeding, and the need for frequent laboratory control, the use of this substance is generally reserved for high risk patients, and/or for long term use. Vitamin K antagonists also demonstrate a notable risk of interaction with other drugs and certain foods, and their use requires monitoring of the patient's blood coagulation status.
Antiplatelet agents, such as aspirin, have been shown to have limited efficacy in preventing DVT (see Chest reference above).
Comparative clinical studies carried out during the course of total hip replacement operations have shown that subcutaneous administration of the thrombin inhibitor hirudin is superior to unfractionated heparin and LMWH in reducing the frequency of total and proximal DVT with no corresponding increase in bleeding (see Eriksson et al in Lancet, 347, 635 (1996) and J. Bone Joint. Surg., Sep., 11 (1996)). However, hirudin is expensive and has an immunogenic potential.
Thus, there is a need for effective treatments of thrombotic conditions such as DVT.